Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma.
Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma.
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DOI：
10.1158/1078-0432.ccr-09-1339
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发表时间：
2009-10-15
期刊：
影响因子：
--
通讯作者：
Timmerman JM
中科院分区：
文献类型：
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作者：
Ansell SM;Hurvitz SA;Koenig PA;LaPlant BR;Kabat BF;Fernando D;Habermann TM;Inwards DJ;Verma M;Yamada R;Erlichman C;Lowy I;Timmerman JM
非霍奇金淋巴瘤的生长可能受到肿瘤-免疫系统相互作用的影响。细胞毒性T淋巴细胞抗原4（CTLA-4）是T细胞活化的负调节剂，其用于抑制抗肿瘤免疫应答。阻断性抗CTLA-4单克隆抗体改善宿主对免疫原性肿瘤的抗性，并且抗CTLA-4抗体易普利姆玛（ipilimumab）（MDX-010）具有针对黑素瘤、前列腺癌和卵巢癌的临床活性。我们在复发/难治性B细胞淋巴瘤患者中进行了伊匹单抗的I期试验，以评估安全性，免疫活性和潜在的临床疗效。治疗包括伊匹单抗3 mg/kg，然后每月1 mg/kg × 3个月（剂量水平1），随后递增至3 mg/kg每月× 4个月（剂量水平2）。18例患者接受治疗- 12例接受较低剂量，6例接受较高剂量水平。伊匹单抗通常耐受良好，常见的不良事件归因于伊匹单抗，包括腹泻、头痛、腹痛、厌食、疲劳、中性粒细胞减少症和血小板减少症。2例患者出现临床缓解，1例弥漫性大B细胞淋巴瘤患者持续完全缓解（31个月以上），1例滤泡性淋巴瘤患者部分缓解持续19个月。在测试的16个病例中的5个（31%）中，在伊匹单抗治疗后，回忆抗原的T细胞增殖显著增加（>2倍）。使用伊匹单抗阻断CTLA-4信号传导在所用剂量下耐受良好，并且在患有B细胞淋巴瘤的患者中具有抗肿瘤活性。因此，有必要进一步评估伊匹单抗单独或与其他药物联合治疗B细胞淋巴瘤患者的效果。
The growth of Non-Hodgkin lymphomas can be influenced by tumor-immune system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation that serves to dampen anti-tumor immune responses. Blocking anti-CTLA-4 monoclonal antibodies improve host resistance to immunogenic tumors, and the anti-CTLA-4 antibody ipilimumab (MDX-010) has clinical activity against melanoma, prostate, and ovarian cancers. We performed a phase I trial of ipilimumab in patients with relapsed/refractory B-cell lymphoma to evaluate safety, immunologic activity and potential clinical efficacy. Treatment consisted of ipilimumab at 3 mg/kg, then monthly at 1 mg/kg × 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly × 4 months (dose level 2). Eighteen patients were treated - 12 at the lower dose and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to ipilimumab including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia and thrombocytopenia. Two patients had clinical responses, 1 patient with diffuse large B-cell lymphoma had an ongoing complete response (31+ months) and 1 with follicular lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%), T cell proliferation to recall antigens was significantly increased (>2-fold) after ipilimumab therapy. Blockade of CTLA-4 signaling using ipilimumab is well tolerated at the doses used, and has anti-tumor activity in patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted.